The arterial chemoreflex responds to low arterial oxygen (hypoxia, Hx) by increasing respiration, sympathetic activity and blood pressure. However, persistent chemoreflex over-activity is also associated with heart failure, hypertension and obstructive sleep apnea (OSA). Patients with OSA and their animal model of chronic intermittent hypoxia (CIH) exhibit augmented chemoreflex, sympathoexcitation and hypertension which are present beyond Hx episodes in normal oxygen and contribute to increased morbidity and mortality. Determining the neurocircuitry responsible for normal chemoreflex function and its aberrant exaggeration is needed to develop targeted therapies to reduce hypertension in cardiorespiratory disease. Peripheral chemoreceptor activation increases chemoafferent discharge in the brainstem nucleus tractus solitarii (nTS), releasing glutamate (Glu) which binds to ionotropic glutamate receptors (iGluRs). The afferent signal is integrated with input from other brain nuclei to produce the final output within the chemoreflex circuit. The paraventricular nucleus of the hypothalamus (PVN) contributes to the integrative chemoreflex autonomic and ventilatory responses. We have established PVN neurons including those that project to the nTS (PVN-nTS) are activated by acute Hx. Hypoxia- activated PVN-nTS neurons primarily contain corticotropin-releasing hormone (CRH) and also oxytocin (OT) and Glu. Within the nTS, CRH receptors (CRFR2) colocalize with OT suggesting PVN activation enhances nTS activity via an interaction of CRH, OT and/or Glu. Chemoafferents also terminate in the area postrema (AP) adjacent to the nTS. The AP sends projections into the nTS (AP-nTS), and AP activation enhances nTS neuronal activity to augment baroreflex function. As a circumventricular organ, the AP is well positioned to contribute to nTS activity, especially during chronic Hx and its elevated circulating hormones or inputs from the PVN. The contribution of the AP in Hx cardiorespiratory response (HxCRR), including CIH-mediated elevation of nTS activity and HxCRR is unknown. Based on our data, our overall hypothesis is that the PVN-nTS pathway is vital to the Hx chemoreflex, and interactions of CRH and OT, and Glu, signaling in the nTS are a primary mechanism. Further, it interacts with the AP-nTS pathway to enhance nTS activity during Hx, and their combined contribution is augmented in CIH. We plan to test our hypothesis by the following specific aims under control conditions and following CIH. We will determine the extent to which 1) PVN projections to the nTS influence cardiorespiratory, neuronal and synaptic responses to hypoxia, and their contribution to cardiorespiratory effects of CIH; 2) excitatory interactions among CRH, OT and Glu mediate the effects of PVN-nTS projections to enhance HxCRR and nTS neuronal and synaptic activity, and 3) AP contributes to Hx cardiorespiratory responses and nTS excitability alone or via an interaction with PVN-nTS inputs. Proposed studies will establish: the importance of neurons in the brainstem and hypothalamus in chemoreflex regulation; their synergistic communication in the nTS in response to chemoreceptor input; and mechanisms that progressively alter their function after CIH.